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Oihana Iriondo, Yarong Liu, Grace Lee, Mostafa Elhodaky, Christian Jimenez, Lin Li, Julie Lang, Pin Wang, Min Yu
Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer that has limited therapeutic options. Thus, developing novel treatments for metastatic TNBC is an urgent need. Here, we show that nanoparticle-mediated delivery of transforming growth factor-β1-activated kinase-1 (TAK1) inhibitor 5Z-7-Oxozeaenol can inhibit TNBC lung metastasis in most animals tested. P38 is a central signal downstream of TAK1 in TNBC cells in TAK1-mediated response to multiple cytokines. Following co-culturing with macrophages or fibroblasts, TNBC cells express interleukin-1 (IL1) or tumor necrosis factor-α (TNFα), respectively...
May 18, 2018: Nature Communications
Anjali Chauhan, Jacob Hudobenko, Abdullah Al Mamun, Edward C Koellhoffer, Anthony Patrizz, Rodney M Ritzel, Bhanu P Ganesh, Louise D McCullough
BACKGROUND: Activation of transforming growth factor-β-activated kinase 1 (TAK1) occurs after stroke and leads to an exacerbation of brain injury. TAK1 is involved in innate and adaptive immune responses, but it has divergent inflammatory effects that are dependent on the cell type in which it is activated. There is a robust infiltration of myeloid cells after stroke; however, the contribution of myeloid TAK1 to cerebral ischemia is currently unknown. We hypothesized that myeloid-specific deletion of TAK1 would protect against ischemic brain injury...
May 17, 2018: Journal of Neuroinflammation
Yu Jiang, Miao Tian, Wenlong Lin, Xinyuan Wang, Xiaojian Wang
Interleukin 17 (IL-17) is a key inflammatory cytokine that plays a critical role in tissue inflammation and autoimmune diseases. However, its signaling remains poorly understood. In this study, we identified serine/threonine kinase 24 (Stk24) as a positive modulator of IL-17-mediated signaling and inflammation. Stk24 deficiency or knockdown markedly inhibited IL-17-induced phosphorylation of NF-κB and impaired IL-17-induced chemokines and cytokines expression. Stk24 overexpression greatly enhanced IL-17-induced NF-κB activation and expression of chemokines and cytokines in a kinase activity-independent manner...
2018: Frontiers in Immunology
Wei Liu, Yuanyuan Jiang, Jing Sun, Shizhong Geng, Zhiming Pan, Richard A Prinz, Chengming Wang, Jun Sun, Xinan Jiao, Xiulong Xu
Autophagy is a conserved cellular process that functions as a first-line defense to restrict the growth of invading parasitic bacteria. As an intracellular pathogen, Salmonella (S) Typhimurium invades host cells through two Type III secretion systems (T3SS) and resides in the Salmonella-containing vacuole (SCV). When the SCV membrane is perforated and ruptured by T3SS-1, a small portion of the Salmonella egresses from the SCV and replicates rapidly in the nutrient-rich cytosol. Cytosolic Salmonella and those residing in the membrane-damaged SCV are tagged by ubiquitination and marked for autophagy through the ubiquitin-binding adaptor proteins such as p62, NDP52, and optineurin...
May 11, 2018: Cell Death & Disease
Boyi Zhang, Da Fu, Qixia Xu, Xianling Cong, Chunyan Wu, Xiaoming Zhong, Yushui Ma, Zhongwei Lv, Fei Chen, Liu Han, Min Qian, Y Eugene Chin, Eric W-F Lam, Paul Chiao, Yu Sun
The senescence-associated secretory phenotype (SASP) can be provoked by side effects of therapeutic agents, fueling advanced complications including cancer resistance. However, the intracellular signal network supporting initiation and development of the SASP driven by treatment-induced damage remains unclear. Here we report that the transcription factor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the persistent SASP signaling...
April 30, 2018: Nature Communications
Junjie Ao, Tao Yuan, Li Gao, Xiaodan Yu, Xiaodong Zhao, Ying Tian, Wenjin Ding, Yuning Ma, Zhemin Shen
Organic ultraviolet (UV) filters, found in many personal care products, are considered emerging contaminants due to growing concerns about potential long-term deleterious effects. We investigated the immunomodulatory effects of four commonly used organic UV filters (2-hydroxy-4-methoxybenzophenone, BP-3; 4-methylbenzylidene camphor, 4-MBC; 2-ethylhexyl 4-methoxycinnamate, EHMC; and butyl-methoxydibenzoylmethane, BDM) on human macrophages. Our results indicated that exposure to these four UV filters significantly increased the production of various inflammatory cytokines in macrophages, particular tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)...
April 20, 2018: Science of the Total Environment
Szu-I Lin, Li-Deh Lin, Hsiao-Hua Chang, Mei-Chi Chang, Yin-Lin Wang, Yu-Hwa Pan, Guay-Feng Huang, Hseuh-Jen Lin, Jiiang-Huei Jeng
BACKGROUND/PURPOSE: Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine involved in the inflammatory processes of dental pulp. IL-8 and urokinase plasminogen activator (uPA) are two inflammatory mediators. However, the role of transforming growth factor beta-activated kinase-1 (TAK1) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways in responsible for the effects of IL-1β on IL-8 and uPA expression/secretion of dental pulp cells are not clear...
April 27, 2018: Journal of the Formosan Medical Association, Taiwan Yi Zhi
Nirav Shah, Sanjay Kumar, Naveed Zaman, Christopher C Pan, Jeffrey C Bloodworth, Wei Lei, John M Streicher, Nadine Hempel, Karthikeyan Mythreye, Nam Y Lee
Acetylation of microtubules (MT) confers mechanical stability necessary for numerous functions including cell cycle and intracellular transport. Although αTAT1 is a major MT acetyltransferase, how this enzyme is regulated remains much less clear. Here we report TGF-β-activated kinase 1 (TAK1) as a key activator of αTAT1. TAK1 directly interacts with and phosphorylates αTAT1 at Ser237 to critically enhance its catalytic activity, as mutating this site to alanine abrogates, whereas a phosphomimetic induces MT hyperacetylation across cell types...
April 27, 2018: Nature Communications
Dayanira Alsina-Beauchamp, Alejandra Escós, Pilar Fajardo, Diego González-Romero, Ester Díaz-Mora, Ana Risco, Miguel A Martín-Serrano, Carlos Del Fresno, Jorge Dominguez-Andrés, Noelia Aparicio, Rafal Zur, Natalia Shpiro, Gordon D Brown, Carlos Ardavín, Mihai G Netea, Susana Alemany, Juan J Sanz-Ezquerro, Ana Cuenda
Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans We describe a new TAK1-TPL2-MKK1-ERK1/2 pathway in macrophages, which is activated by Dectin-1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C...
April 16, 2018: EMBO Molecular Medicine
Jun Zhou, Jiying Zhong, Zhenxing Huang, Meijuan Liao, Sen Lin, Jia Chen, Hongtao Chen
Renal fibrosis is a common and characteristic symptom of chronic kidney disease (CKD). However, the molecular mechanisms of renal fibrosis remain elusive. Ischemia injury, as a major cause of AKI, deserves more attention in order to improve the knowledge of AKI-induced fibrosis. Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) interacts directly with TGF-β, which play a critical role in the progression of fibrosis. Therefore, the present study aimed to investigate the role of TAK1 in the pathogenesis of ischemia-induced renal fibrosis...
April 16, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Sarang Tartey, Prajwal Gurung, Tejasvi Krishna Dasari, Amanda Burton, Thirumala-Devi Kanneganti
Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for several kinases such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in Ptpn6spin mice...
April 9, 2018: Journal of Clinical Investigation
Rui Peng, Wen Dai, Yan Li
Clinical and experimental studies suggested that testosterone or estradiol alone supplementation may have antidepressant-like effects. However, the synergistic effect of testosterone/estradiol on the treatment of depression and the underlying mechanism remain largely unknown. Here, we hypothesized that an appropriate dosage of testosterone combined with estradiol may became a new therapeutic strategy in depression. Our results indicated that an appropriate testosterone/estradiol ratio of 10:1 (10-8  mol/L testosterone and 10-9  mol/L estradiol) was found, which has a significant synergistic anti-apoptotic effect on PC12 cells injury stimulated by corticosterone...
April 3, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Alaa Refaat, Mohamed Owis, Sherif Abdelhamed, Ikuo Saiki, Hiroaki Sakurai
HuT-102 cells are considered one of the most representable human T-lymphotropic virus 1 (HTLV-1)-infected cell lines for studying adult T-cell lymphoma (ATL). In our previous studies, genome-wide screening was performed using the GeneChip system with Human Genome Array U133 Plus 2.0 for transforming growth factor-β-activated kinase 1 (TAK1)-, interferon regulatory factor 3 (IRF3)- and IRF4-regulated genes to demonstrate the effects of interferon-inducible genes in HuT-102 cells. Our previous findings demonstrated that TAK1 induced interferon inducible genes via an IRF3-dependent pathway and that IRF4 has a counteracting effect...
April 2018: Oncology Letters
Olga Sokolova, Thilo Kähne, Kenneth Bryan, Michael Naumann
Transforming growth factor-β (TGFβ)-activated kinase 1 (TAK1) plays a central role in controlling the cellular pro-inflammatory response via the activation of the nuclear factor κB (NF-κB)- and mitogen-activated protein (MAP) kinases-dependent transcriptional programs. Here, we show that depletion of TAK1 and the TAK1-binding proteins TAB1 and TAB2 affects NF-κB, JNK and p38 phosphorylation and suppresses NF-κB activity in AGS cells infected with Helicobacter pylori or stimulated with the cytokines TNF and IL-1β...
March 6, 2018: Oncotarget
Han Gyung Kim, Mi Yeon Kim, Jae Youl Cho
ETHNOPHARMACOLOGICAL RELEVANCE: Alisma canaliculatum A.Braun & C.D.Bouché, distributed in Korea, Japan, China, and Taiwan, is a traditional medicine. In particular, the stem and root of Alisma canaliculatum A.Braun & C.D.Bouché are prescribed to relieve various inflammatory symptoms resulting from nephritis, cystitis, urethritis, and dropsy. AIM OF STUDY: However, the curative mechanism of Alisma canaliculatum A.Braun & C.D.Bouché with respect to inflammatory symptoms is poorly understood...
March 21, 2018: Journal of Ethnopharmacology
Yichao Zhao, Lingchen Gao, Longwei Xu, Renyang Tong, Nan Lin, Yuanyuan Su, Yang Yan, Yu Gao, Jie He, Lingcong Kong, Ancai Yuan, Ying Zhuge, Fang Wang, Jun Pu
Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, insulin resistance and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here we report that USP4 expression was dramatically downregulated in the livers from NAFLD patients and different NAFLD mouse models induced by a high fat diet (HFD) or a genetic deficiency (ob/ob) as well as in palmitate-treated hepatocytes...
March 23, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
James H Matthews, Xiao Liang, Valerie J Paul, Hendrik Luesch
Resistance to chemotherapy is a major obstacle in the treatment of a wide array of different types of cancer. Chemotherapeutic drug resistance is achieved by cancer cells by a variety of different mechanisms, which can be either compound specific or general. An emerging mechanism for nonspecific chemotherapeutic drug resistance relies on hyperactivity of the transcription factor Nrf2. Normally Nrf2 levels are tightly regulated by the ubiquitin-proteasome system; however, mutations in genes responsible for this regulation are common in many cancer types, resulting in increased expression of Nrf2, activation of its downstream target genes, and resistance to a variety of chemotherapeutic agents...
March 22, 2018: ACS Chemical Biology
Li Ma, Li Feng, Xiaoping Ding, Yongwang Li
The present study aimed to investigate the effect of Toll-like receptor 4 (TLR4) on SiHa human cervical cancer cells and its potential molecular biological mechanisms. The expression of TLR4 following treatment with lipopolysaccharide (LPS) in in SiHa cervical cancer cells was detected by quantitative polymerase chain reaction (qPCR). LPS-induced cell proliferation and apoptosis were detected by MTT assay as well as staining with propidium iodide (PI) and Annexin V/PI double staining. qPCR was performed to analyze the expression levels of tumor necrosis factor receptor-associated factor 6 (TRAF6) and transforming growth factor-activated kinase 1 (TAK1) genes...
March 2018: Oncology Letters
Jing Sun, Yarong Mu, Yuanyuan Jiang, Ruilong Song, Jianxin Yi, Jingsong Zhou, Jun Sun, Xinan Jiao, Richard A Prinz, Yi Li, Xiulong Xu
Autophagy plays a central role in degrading misfolded proteins such as mutated superoxide dismutase 1 (SOD1), which forms aggregates in motor neurons and is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is activated when UNC-51-like kinase 1 (ULK1) is phosphorylated at S555 and activated by AMP-activated protein kinase (AMPK). Autophagy is suppressed when ULK1 is phosphorylated at S757 by the mechanistic target of rapamycin (mTOR). Whether p70 S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, can also regulate autophagy remains uncertain...
March 14, 2018: Cell Death & Disease
Qiaojie Chen, Shaokun Wu, Yaojun Wu, Liang Chen, Qingjiang Pang
BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease that with the complication of disability, while inflammation is the important response of OA. MiR-149 was down-regulated in the OA tissues, while the potential mechanism of miR-149 in OA is unclear. METHODS: A total of 20 OA patients and 20 healthy persons were enrolled in the present study. Real-time PCR was used to detect miR-149 and the mRNA expression of TAK1, western blot was used to detect the protein expression of TAK1...
May 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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